Disease Team Planning
Human amniotic fluid stem cells are a reliable and scalable source of ethically neutral stem cells for tissue protection and repair. ALI is a serious lung disease that is refractory to current supportive therapy including surfactant and corticosteroids. Recent work by others and us supports the concept that ALI may be amenable to stem cell therapy with hAFSC during the acute phase. We propose an ALI disease team planning award based on the concepts that: AFSC are efficiently taken up and can integrate into the lung following intravenous injection. The efficiency of lung uptake and integration is increased following acute lung injury. Tissue injury can be ameliorated following AFSC intravenous injection. Because of its high incidence, acute nature, severity and fatality, ALI is a near ideal candidate disease to advance CIRM’s primary goal for the Disease Team Initiative, advancing a stem cell-derived therapy or diagnostic toward the clinic.
Statement of Benefit to California:
Developing a stem cell therapy program on human amniotic stem cells for acute lung disease in California will provide an access advantage to the people of California for this new therapy. It will also provide a competitive advantage for development of an amniotic fluid stem cell based biotechnology in California.
Executive Summary The Principal Investigator (PI) for this proposal plans to assemble a team of investigators to study the use of human amniotic fluid stem cells (AFSC) to treat patients with Acute Lung Injury (ALI). ALI is serious lung disease that is refractory to current supportive therapy including surfactant and corticosteroids. Scientific rationale is based on some recent studies which suggests that, similar to mesenchymal stem cells (MSC), AFSC have ability to ameliorate tissue injury in some organs. The mechanism of action is believed to be due to secretion of anti-inflammatory cytokines such as IL-1 receptor antagonist by AFSC . The reviewers felt that the use of AFSC for therapeutic applications is premature at this time. The PI has provided minimal background and preliminary data in the proposal supportive of the concept to use AFCS for the treatment of ALI. The PI has not provided any justification as to why AFSC might be better than MSC or other stem cell sources. Moreover, reviewers were concerned about the lack of details in the proposal on the disease planning process and on the disease indication. It was unclear which type of ALI will be treated with this approach. It was pointed out that the techniques to harvest, characterize, store and infuse AFSC have not been established. Although the PI has extensive experience in the field of lung injury and repair, he/she has no experience in the isolation, banking, testing, storage, donor screening or propagation of AFSC. Overall, reviewers felt that from the information provided in the proposal, it is difficult to see how a competitive application could be developed that could lead to a clinical trial in the required time frame. Reviewer One Comments Concept: The PI proposes to bring together a team to study the use of human amniotic fluid stem cells (AFSC) to treat patients with Acute Lung Injury (ALI). The work is premature, not well developed and not likely to lead to a clinical trial within the next 5 years. Techniques to harvest, characterize, store and infuse AFSC have not been established. Preclinical studies in ALI have not been peformed. The type of ALI that might benefit from this therapy is not described. Principal Investigator: The PI, Dr. David Warbuton has extensive experience in the field of lung injury and repair. It is not clear, however, that he has expertise in the isolation, banking, testing, storage, donor screening or propagation of AFSC. Planning Approach: There is very little information about the actual design or focus of the planning team. This part of the application is weak and insufficient to determine the plans of the group. From the information presented it is difficult to see how a competitive application could be developed in the next year. Reviewer Two Comments Concept: Concept: This proposal describes the possible use of human amniotic fluid stem cells (AFSC) for treatment of ALI. AFSC have been shown to be similar to MSC, they seem to have an ability to ameliorate tissue injury in several organs. The mechanism of action is thought, at least in part, to be due to secretion of protective cytokines such as IL-1RA, and prolonged integration may not be necessary for the response. Preliminary data: • AFSC are effective in tubular necrosis of the kidney in mice • State that AFSC are efficiently taken up and integrate into the lung tissue • following IV injection. Increased rate of uptake after lung injury. • Tissue injury reduced after AFSC IV injection Strengths: • Preliminary results in mouse model of kidney suggest some ability of AFSC to reduce inflammatory response. • Dr. Warburton has previously organized numerous workshops focused on lung development and repair. Weaknesses: • No discussion of why AFSC might be better than MSC or other stem cell sources. • Minimal details provided, mostly promises that the process of multidisciplinary team building workshop, team project selection, coordination and collaboration, document preparation will be concluded well prior to deadline for proposal submission. • Minimal background and preliminary data. Only two papers referenced. • Many of the various sections of the application are repeats of other parts or are very short. Evidenced by: • Public abstract • Summary of benefit to California (one sentence long). • Budget justification (3 lines) • Other research support (1-2 sentence descriptions, no specific aim listed). Principal Investigator: PI: Dr. Warburton directs the Developmental Biology, Regenerative Medicine, and Surgery Program at the Saban Research Institute, CHLA. He has over 30 years of experience in lung research, 300 publications. The Saban program has 15 interdisciplinary faculty, and collaborates with stem cell programs at USC, Wake Forest, Newcastle and Imperial college in England. Dr. Warburton is very well funded by NHLBI in the area of lung injury and repair, including directing a program project in this field. On the advisory board are members from Amgen, Abraxis, and Novartis. Planning Approach: Planning Approach: • Conduct first workshop to coordinate efforts of ALI experts in California.Participants will submit research sub-proposals • Assemble interdisciplinary team. Dr. Warburton plans to identify colleagues at CHLA, USC, UCLA, UCSF,and UCSD to collaborate on AFSC therapy for ALI. • Second workshop to finalize specific aims and milestone details • Optimize infrastructure to harvest, store, and deliver GMP AFSC.. Collaborate with Atala group in North Carolina. Discuss with industry and political interests • “Conclude” proof of principle in animal models • Consult with Regulatory agencies. Ascertain safety requirements..Coordinate IND filing with FDA • Develop a plan and timeline to conduct phase I and II trials .Identify focused ALI patients. Adults-radiation therapy.. Children BPD or sickle cell with acute chest syndrome.